Intraportal and intrasplenic transplantation of hepatocytes have provided support for rats and outbred dogs in acute liver failure until recovery occurs. Autologous or syngeneic hepatocytes are more efficient than allogeneic or xenogeneic hepatocytes, but neither the role of immunosuppression nor the ability of the transplanted cells to function long term has been systematically evaluated. We will study the functional capacity of transplanted hepatocytes and their ability to improve the survival of genetically defined rats and N.I.H. miniature pigs with acute or chronic liver failure. Three different experimental variables will be examined in order to improve the success of hepatocyte transplantation prior to acute liver failure or after development of cirrhosis: (1) The contribution of histocompatibility will be studied by using syngeneic (autologous in the pig), allogeneic or xenogeneic hepatocytes with or without the immunosuppressant Cyclosporin A (CSA) at 20 mg/Kg; (2) The effect of the proliferative status of hepatocytes at the time of transplantation will be examined by comparing normal hepatocytes to those harvested 3 days after 70% partial hepatectomy; and (3) The ability of regenerating liver extract (RLE) to improve the number of hepatocytes that survive and proliferate. Fourteen days after intrasplenic transplantation of 3 x 10 to the seventh hepatocytes in the Lewis rat and 25 x 10 to the eighth hepatocytes in the inbred miniature pig (splenic artery ligated), anoxic acute liver failure will be produced by hepatic artery ligation (rat) or by occlusion of the hepatic artery and portal vein for 60 minutes (pig). Cirrhosis and chronic liver failure will be produced in both rat and pig with intermittant dimethylnitrosamine (DMNA) administration over 4 weeks. Successful transplantation will be measured by recipient survival, biochemical improvement, autoradiographic evidence of proliferaiton and histological evidence of hepatocyte organization within the spleen. Recipient serum will also be examined for cytotoxic antibody to the hepatocyte donor.